Tlie striatum is mostly comprised of GABAergic medium spiny projection neurons (MSNs) tlnat differ in thieir neuropeptide expression and form two major efferent patiiways. MSNs that contain the neuropeptides dynorptiin and substance P are part of the striatonigral, or 'direct', pathway whereas MSNs that contain the neuropeptide enl<ephalin are part of the striatopallidai, or 'indirect', pathway. Psychostimulant-induced alterations in the striatum are thought to be critical in the development and maintenance of drug addiction; however, the role of specific striatal cell populations is not clear. Nonetheless, recent evidence suggests that striatopallidai neurons may be especially important for the long-term changes in brain and behavior produced by drugs. For example, studies using immediate early gene expression as an indicator of neuronal activity found that while mere psychostimulant exposure is sufficient to increase activity in striatonigral neurons, only drug exposure under conditions that lead to forms of drug-induced behavioral plasticity, such as psychomotor sensitization, also activates striatopallidai neurons. The overall aim of the proposed experiments is to use novel molecular and genetic targeting approaches to directly examine the involvement of striatopallidai MSNs in drug-induced molecular changes and behavioral plasticity. It is hypothesized that recruitment of striatopallidai neurons is critical for the long-term changes in striatal gene expression induced by psychostimulants, as well as in the development and expression of psychomotor sensitization and the escalation of drug self-administration behavior. This work will help to elucidate the contribution of striatopallidai medium spiny neurons in the processes that underlie addiction; In addition, precise identification ofthe neural circuits that regulate the transition to addiction should be useful for guiding the development of future treatments for addicts.